Inflammation is the foundation for cancer and degenerative/autoimmune diseases. Small changes in diet and exercise, e.g. omega-3 oils, vitamin D, low starch, and maintaining muscle mass, can dramatically alter predisposition to disease and aging, and minimize the negative impact of genetic risks. Based on my experience in biological research, I am trying to explain how the anti-inflammatory diet and lifestyle combat disease. 190 more articles at http://coolinginflammation.blogspot.com

Anti-Inflammatory Diet

All health care starts with diet. My recommendations for a healthy diet are here:

Thursday, April 30, 2009

....But, if a doctor emailed me pleading for any ideas that I had to save a bunch of patients suffering from acute respiratory distress syndrome (ARDS) from Tamiflu-resistant H1N1, my first response would be to suggest therapies designed for ARDS from other origins, e.g. burns, septicemia, etc.

Cytokine Storms Are Out of Control
When too much tissue is injured, the local, molecular communication that normally occurs just between cells, spills into the blood stream and becomes potentially lethal. That is what happens in anaphylactic shock. It is also what happens in cytokine storms, where inflammatory cytokines that are normally short-lived and processed locally to progress into recovery, erupt into the blood stream and impact distant organs.

Major disruption of body function by aggressive blood infections or burns over most of the body, will be lethal without heroic medical interventions. These are injuries beyond the evolved adaptations of mammals. Until recently there were no survivors.

Influenza has been around for a long time. Humans, other mammals and birds get the flu and get over it. Many body cells become infected, antibodies specific to the virus are produced within about a week, the infected cells are killed, the virus is digested and life goes on.

People die from the flu, because an opportunistic pathogen causes a lethal secondary infection, or the body over-reacts and damages itself in attempts to attack its own infected cells. This is a cytokine storm.

Silence the Storms
Cytokine storms can be weathered by blocking the signaling system. Cytokines are just small proteins that are complementary in shape to corresponding protein receptors that penetrate through the surface membranes of cells throughout the body. Binding of cytokine to receptor changes the shape of the receptor and transmits a signal into the cytoplasm of the receptive cell. This turns on aggressive behavior of immune cells and triggers more inflammatory signaling in other cells. This causes fever, malaise, etc.

...But, I was the one the doctor is pleading with to save the people. And I know that there is more to cytokine signaling than just cytokines and receptors. There are also heparan sulfate proteoglycans (HSPGs). Cytokines are not supposed to be broadcast throughout the body. Cytokines function in the space between cells, the extracellular matrix. Polysaccharides attached to membrane proteins, HSPGs, are secreted at one end of the cells, sweep across the surface and are taken back up at the other end. Cytokines have heparan-binding domains and so they stick to the heparan and are swept along. Cytokines can move from one cell to another as the sweeping HSPGs of adjacent cells come in contact.

HSPGs Mediate Cytokine Signaling
The critical point here is that cytokines bind to their receptors with the heparan between -- the cytokine and receptor are like two halves of a bun and the hot dog is the heparan. In fact the heparan bridges two cytokine/receptor complexes to make an active, signaling pentamer.

Heparin Can Block Cytokine Signaling
Heparin is a fragment of heparan sulfate produced by enzymatic degradation of HSPG. Commercial heparin, used to block blood clotting, is obtained from the mast cells of lungs and intestines of hogs and cattle. The mast cells release heparin and histamine in response to parasites or pollen. Since heparin is a short version of heparan sulfate, it can block the formation of active cytokine/receptor complexes.

Heparin is used in a mist to treat the lungs of burn patients. It is also injected into some infertility patients to suppress inflammation that is inhibiting implantation and gestation. It is also effective in treatment of autoimmune inflammation in Crohn’s disease. I think it should be tested as a therapy for H1N1 cytokine storms. It may be useful in nebulizing mists and oral treatment of intestines.

Berberine Binds to HSPGBerberine is a phytochemical from Barberry traditionally used in the treatment of intestinal infections and arthritis. It also binds to heparan sulfate to form fluorescent complexes visible in microscopy. Berberine-treated mast cells glow brightly. Heparan sulfate can also be detected in Alzheimer’s plaque, atherosclerotic plaque and prion complexes. Because berberine binds to heparan sulfate, it should also disrupt cytokine signaling. It has been used successfully in treatment of septicemic ARDS.

Curcumin Blocks NFkB
One of the most potent chemicals that blocks inflammatory signaling via the inflammatory transcription factor, NFkB, is curcumin. Curcumin is a major component of the spice turmeric. Oral curcumin can be enhanced by co-administration of black pepper, because the piperine in pepper inhibits intestinal inactivation.

25 comments:

Hi Dr. Art, nice information! So a quick question for you? If you were taking an 81mg Baby Aspirin as a daily regimen and you contract any flu, much less swine flu or the H5N1 Avian strains, what would you do?

Here is my thinking: On the one hand, you have a small amount of substance that is supposed to decrease inflammation a bit and if you stop it suddenly, can have a rebound negative effect. You also have a virus that responds to anti-inflammatories at the cytokine storm stage. But, aspirin can contribute to a potentially fatal Reyes Syndrome when taken during a viral infection.

Hi Pooti,You are asking all of the same questions that I am pondering. No one seems to understand the aspirin/Reyes/juvenile relationship. I just looked at it again recently and there is still no concensus. Adults don't seem to have the problem and so aspirin seems to cause them less problems.I have been taking the 81mg baby aspirin for the last couple of years, but now have my doubts. It probably doesn't make sense to trust some of the medical studies, when I nitpick most to meaninglessness.

As of this minute, my personal thoughts on the H1N1 is that it is similar to typical seasonal epidemics, with the exception that it can cause the cytokine storm. That means that 90% of people won't be concerned. The remainder can have problems with secondary infections and a small minority will have the life-threatening cytokine storm. The problem is that most medical facilities don't know how to recognize and treat the storms. The pharmaceutical industry always takes the lead in these situations and only new drugs are tested. The solutions are all in simple things such as spices, but there is no money in it and research on berberine, for example, will be prohibited, because it would eliminate a profit center.

I think for most people the baby aspirin isn't going to make a difference.

Those with metabolic syndrome have a not-so-secret weapon. Their obesity has created a massive immune system organ of their adipose tissue. It is loaded with lymphocytes that are pumping out inflammatory cytokines. There is some evidence that fasting will shift all of this immune signaling away from inflammation. At the first sign of flu, it would seem prudent for these people to go into a medically supervised fast. The supplements recommended for an anti-inflammatory diet should continue to help. Under these conditions, I don't know if a cytokine storm is possible.

Unfortunately, there is no data on the inflammatory status of H1N1 victims who died. Were they lean or obese? Did they have allergies, diabetes or autoimmune diseases? They were predominantly not the typical young or old.

Dr Ayers,Is there a strategy to enlist HSPs, the molecular chaperones, for cytoprotection at the local level?

IMO, fasting can also limit the proliferation of methanogens (hydrogen producers), helpful in controlling opportunistic infections.

While reading your post on "anti-inflammatory diet and life style" I sense a certain dissonance between the recommending of fasting but having reservation about consuming saturated fat. Isn't fasting the actual consumption of the body's fat storage which is primarily SFA?Regards,

JohnN, I have no problems with saturated fats. I just feel a little hesitant at saying that they are healthy, when the medical establishment is so adamant about there risks. So I hedge and say that if they are a problem, it is only for those who already have chronic inflammation. The evidence against saturated fats is far weaker than it is against omega-6 oils.

I don't actually know what circulating lipids are being encountered by lymphocytes and other cells that can produce prostaglandins/eicosanoids when fasting. Do the stored lipids and mobilized lipids have the same profile as those eaten to make the stored fat? That would mean that as fats are mobilized, you would relive your bad eating habits (similar to fat-soluble pesticides). Those are interesting questions.Art

Oh, I'm with you on the detox. And just the idea of the "cosmic pizza grease" is enough to put me off Alli/orlistate for any reason (I lost my excess weight far easier with low carb eating and that's what I'm committed to). I just thought it was a rather funny potential "off-label" use for a pretty useless drug.

Anna,I think that your intuition on this scatological joke of a weight loss product is correct.

Fat soluble toxic compounds are a potential health threat on their way into and back out of fat reserves. Bile serves to return the compounds to the gut for another round of uptake. The uptake blockers could short circuit the return. This might be useful, but it would seem that the entire reserves would need to be depleted to remove all of the compound. Otherwise just a small portion would be turned over at some unknown slow rate.

It might be useful, but would require some development and creative PR.Art

There is a group of lyme patients that experiences ALS-like muscle wasting. When some of these people are treated with normal doses of IV drugs and experience a herxheimer reaction, the wasting increases. If these doses are continued, they will die faster. On the other hand, if put on much lower doses, pulsed, a stable condition can be achieved.

The herxheimer reaction has been used as a model of sepsis, and is considered a cytokine storm, I believe.

This produces a catch 22 situation that lower doses may not produce enough killing action to be effective, the treatment might have to be forever (expensive, other hazards). Orals do not seem to work on this group.

So, your observation that medicine does not seem to understand or know how to treat cytokine storms appears to apply in this situation. It would sure be nice if someone would figure this out! Otherwise, there is a lot of treading water going on, with no hope of reaching the shore.

"[...] a practical and inexpensive regimen consisting of high-dose salicylates, spirulina, and N-acetylcysteine, initiated at the earliest feasible time, may prove to have life-saving efficacy when the next killer influenza pandemic strikes."

Hi Dr. Ayers,I am an H1N1 (Swine Flu) survivor with chronic asthma and weight issues. I was infected on my trip to Cancun in April of 2009...and took about 2 full months to recover. Initially I thought I had a cold from the air conditioned room but on the plane home two days after the onset of symptoms I thought it might be malarya. As swine flu was still not in the news. The day after returning i was admitted to the hospital and given basic inhalers and oxygen for support...I'm not sure if they helped much or just being there helped me relax...They had asked i remain overnight for observation as my oxygen levels in my blood stream were low...But I really wanted to go home...Which I did and was told to remain in isolation.That night I had a craving for tobacco but since Mexico had not been able to even take a puff...I did some initial research online and discovered an article you had writen about H1N1 and Tobacco as an anti-inflamatory. Well that article gave me at least the "nerve" to try.Initially I coughed a few times...But I did begin to feel like I was breathing better. Over the course of the next few weeks I would continue to have 1-2 cigarettes during the day and this really seemed to have a psoitive influence in my asthma and breathing...it seemed to dry up all the lose particles in my airway...and I had no weeziness.I would like to talk to you about my experience as I truly feel this played an important role in my recovery. Cheers and thank you!

Can u comment on the theory that whiskey /red wine is a solution to calm the cytokine storm..russian doctors seemed to have suggested that to footballfans visiting WalesIn india when we get a fever we are put on a diet of kanji (brown, unpolished rice and its water) with pickle (turmeric , pepper, chillies) as ingredients...)ur comment on cumin seems to tie in with that.Hope u can comment on the whiskey..Any excuse for a party ..eh ??!!

Alcohol and particularly phytochemically augmented brews like whiskey and red wine, are very complex and their impact on the immune system, for me at least, is unpredictable.

The effects of a stiff shot of alcohol can have an immediate inflammatory response as cells are killed in direct contact with the lethal spirits. The warmth sensation also indicates that a secondary vagus nerve response may result in anti-inflammatory opiod production. Then there are the effects on the liver and so on... too complex to predict the impact on cytokine storms.

Then there are the numerous additional phytochemicals from oaken casks and or grape skins. These may have dramatic effects on gut and gut flora. What is the impact on common conditions such as H. pylori infections and celiac? What about the biofilms?

Whiskey provides an interesting dilemma and I don't know the answer. I wish that all of the national health programs that could get the useful information on simple treatments would pool their information and come up with cheap cures. Maybe the answer is the nicotine from a single smokeless cigarette. That would be far cheaper and perhaps for effective than multibillion dollar antiviral and vaccine programs.

You may have covered this & I just haven't gotten to it yet, but I was looking at the recent research on elderberry extract's ability to bind H1N1 and it looks very promising to my uneducated eye. Would be interested in your pov!

Very interesting blog. Anecdotal evidence is that I had some kind of virus with diarea, fever, chest pain, shortness of breath and severe muscle aches and sambucol and some supplements such as you suggested may have helped. I felt awful and was massively congested. For a couple of days I felt the worst I have felt since I had Dengue Fever in Mexico. I was worried about the Sambucol causing a cytokine storm (I had read plenty about it on flutrackers before taking it). In the end I decided that if it inhibted the virus, then my body probably wouldn't do a cytokine storm but I definitely ended up incredibly congested and short of breath. That said, I took other things that may have canceled out the pro-cytokine part of sambucol. In addition I also took fish oil, bromelain, curcumin, l-carnosine and a large dose of vitamin C. As I said, purely anecdotaland while I'm sure I had some kind of flu (mainly because of the muscle aches) I do suspect it was swine flu but cannot be sure.Also: I read somewhere that being obese is indeed a risk factor for mortality if you are admitted to the ICU positive for H1N1. So you guessed right.

Listen to my podcast on Jimmy Moore's Livin' La Vida Low Carb Show

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About Me

I grew up in San Diego and did my PhD in Molecular, Cellular and Developmental Biology (U. Colo. Boulder). I subsequently held postdoctoral research positions at the Swedish Forest Products Research Laboratories, Stockholm, U. Missouri -Colombia and Kansas State U. I was an assistant professor in the Cell and Developmental Biology Department at Harvard University, and an associate professor and Director of the Genetic Engineering Program at Cedar Crest College in Allentown, PA. I joined the faculty at the College of Idaho in 1991 and in 1997-98 I spent a six-month sabbatical at the National University of Singapore. Most recently I have focused on the role of heparin in inflammation and disease.